Glucocorticoid-induced TNFR-related protein (“GITR”) is a member of the Tumor Necrosis Factor Superfamily (TNFRSF) which includes more than 20 type I transmembrane proteins, several splicing variants and several viral proteins, all of which have a cysteine-rich domain as a common structural feature. The extracellular domain (ECD) of GITR consists of 3 cysteine-rich domains (CRDs), followed by a transmembrane domain (TM) and an intracellular domain (ICD).
GITR expression is detected constitutively on murine and human CD4+CD25+ regulatory T cells which can be further increased upon activation. In contrast, effector CD4+CD25− T cells and CD8+CD25− T cells express low to undetectable levels of GITR, which is rapidly upregulated following T cell receptor activation. Expression of GITR has also been detected on activated NK cells, dendritic cells, and macrophages. Signal transduction pathway downstream of GITR has been shown to involve MAPK and the canonical NFicB pathways. Various TRAF family members have been implicated as signaling intermediates downstream of GITR (Nocentini et al. (2005) Eur. J. Immunol., 35:1016-1022).
Cellular activation through GITR is believed to serve several functions depending on the cell type and microenvironment including, but not limited to, costimulation to augment proliferation and effector function, inhibition of suppression by regulatory T cells, and protection from activation-induced cell death (Shevach and Stephens (2006) Nat. Rev. Immunol., 6:613-618). Ko et al. ((2005) J. Exp. Med., 202:885-891) first demonstrated that an agonistic monoclonal antibody against mouse GITR effectively induced tumor-specific immunity and eradicated established tumors in a mouse syngeneic tumor model. Additionally and/or alternatively, an anti-mGITR which has functional Fc effector activity has been shown in some preclinical models to deplete regulatory T cells, as well as enhance T effector cell proliferation and cytokine secretion in select tumor environment. These findings suggest that an agonistic antibody to mGITR can disrupt immune tolerance balance, which in turn will allow T cells to combat tumors and persistent viral infections. However, studies to date have largely focused on use of surrogate antibodies in rodent systems. Due to the divergence of structure among mouse and human GITR, it is unknown whether findings seen with surrogate studies in mouse would translate to modification of human GITR function.